Efficacy of Pharmacological Treatment of Working Memory Impairment After Traumatic Brain Injury: Evaluation With fMRI

Traumatic Brain Injury Clinical Trial

Official title:

Efficacy of Pharmacological Treatment of Working Memory Impairment After Traumatic Brain Injury: Evaluation With fMRI

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00489892
• Other study ID #: D-437-02
• Secondary ID: 0120020166M-166-
• Status: Recruiting
• Phase: N/A
• First received: June 20, 2007
• Last updated: July 23, 2007
• Start date: August 2003
• Est. completion date: December 2008

Study information

• Verified date: July 2007
• Source: Kessler Foundation
• Contact: Elie P Elovic, M.D.
• Phone: (973) 243-6815
• Email: eelovic[@]kmrrec.org
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This study is designed to examine the effects of a wake-promoting agent (Modafinil) on working memory (WM) in persons with moderate to severe TBI utilizing a double blinded placebo controlled methodology. Our approach is to evaluate participants with BOLD fMRI and a limited neuropsychological battery to examine WM performance before and after pharmacological intervention.

Hypotheses

1. Because increased cognitive effort (as a function of decreased efficiency after TBI) is presumed to underlie fMRI activation dispersion that is seen during central executive WM tasks, we anticipate an attenuation of cerebral activation in prefrontal cortex during pharmacological intervention with Modafinil when compared to placebo administration on the mPASAT and vigilance testing.

2. There will be a correlation between the decreased dispersion of the fMRI signal on scans and improvement in neuropsychological measures when individuals are on Modafinil that is not seen when they are taking placebo.

Description:

Work from our institution has shown that moderate and severe TBI subjects demonstrate an altered cerebral representation when they attempt to process a verbal WM task. Specifically, our data show a post-TBI pattern of activation that is dispersed and more lateralized to the right hemisphere, as compared to healthy controls. Taken together, we interpret these findings to mean that it is requires more cerebral resources for TBI subjects to process tasks that were previously more automatic. In other words, their processing is less efficient. This is consistent with TBI patients’ self-reports of needing to expend greater cognitive effort to perform such tasks, both in the lab and in everyday life. Our preliminary data was the first step in understanding the cerebral substrate of these difficulties. However, simply indicating that individuals with TBI have a WM problem is not enough. The development of targeted interventions to ameliorate these deficits is the next step in the treatment process.

The present proposal has important implications for TBI rehabilitation. One of the major goals of cognitive remediation is to help TBI patients learn new information more accurately and efficiently, and to improve their performance in activities of everyday life. 123 Because WM impairments are so prevalent in TBI, the present study can help to shed light on potential treatment alternatives for these potentially devastating problems. In spite of the prevalence and popularity of cognitive remediation strategies and procedures, there remains little empirical support for their efficacy, and virtually no understanding of the underlying neurocognitive processes that facilitate intervention. The ability to develop a potentially efficacious treatment modality, which has a solid foundation, would be immensely beneficial.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

We will include only those subjects who have sustained moderate to severe initial injuries, as defined by an initial 24-hour Glasgow Coma Scale 128 scores below 13. In the event that a GCS score is not available, subjects will only be included if there is sufficient medical documentation that would allow for a post-hoc estimation of initial GCS, or if other confirmatory data (e.g., positive anatomic neuroimaging findings, focal neurologic signs) are available. Individuals with a history of prior moderate to severe head injury, stroke, seizures, severe psychiatric disturbances (i.e., those known to influence memory performance, such as schizophrenia, bipolar disorder), or drug abuse will not be included as subjects. In addition, a score of 11 or greater on the Mini Mental Status Exam will be required to insure that subject can participate effectively in the study protocol. Because of potential effects on cognition and hemodynamic response, subjects currently taking benzodiazepines, narcotics, neuroleptics, anticonvulsants, antispasticity agents or psychostimulants will not be included.

In addition, any patient that is on medications that may interact with any of the study medications (e.g. birth control bills or cyclosporin). Psychiatric symptoms and substance abuse history will be obtained using a structured psychiatric interview, the Diagnostic Interview Schedule 129DIS. In addition patients with history of drug dependency, hypertension out of control, significant cardiac disease, or inability to undergo MRI. (e.g. metalworker, Medtronic infusion pump)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Injuries
• Severe Traumatic Brain Injury
• Traumatic Brain Injury

Intervention

Drug:
• Modafinil

Locations

Country	Name	City	State
United States	Kessler Medical Rehabilitation Research & Education Corporation	West Orange	New Jersey

Sponsors (3)

Lead Sponsor	Collaborator
Kessler Foundation	Cephalon, University of Medicine and Dentistry of New Jersey

Country where clinical trial is conducted

United States, 

References & Publications (10)

Baddeley A. Working memory. Science. 1992 Jan 31;255(5044):556-9. Review. — View Citation

Guerrero JL, Thurman DJ, Sniezek JE. Emergency department visits associated with traumatic brain injury: United States, 1995-1996. Brain Inj. 2000 Feb;14(2):181-6. — View Citation

Levin HS, Gary HE Jr, Eisenberg HM, Ruff RM, Barth JT, Kreutzer J, High WM Jr, Portman S, Foulkes MA, Jane JA, et al. Neurobehavioral outcome 1 year after severe head injury. Experience of the Traumatic Coma Data Bank. J Neurosurg. 1990 Nov;73(5):699-709. — View Citation

McAllister TW, Saykin AJ, Flashman LA, Sparling MB, Johnson SC, Guerin SJ, Mamourian AC, Weaver JB, Yanofsky N. Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study. Neurology. 1999 Oct 12;53(6):1300-8. — View Citation

McDowell S, Whyte J, D'Esposito M. Working memory impairments in traumatic brain injury: evidence from a dual-task paradigm. Neuropsychologia. 1997 Oct;35(10):1341-53. — View Citation

Ponsford J, Kinsella G. Attentional deficits following closed-head injury. J Clin Exp Neuropsychol. 1992 Sep;14(5):822-38. Erratum in: J Clin Exp Neuropsychol 1995 Aug;17(4):640. — View Citation

Schootman M, Fuortes LJ. Ambulatory care for traumatic brain injuries in the US, 1995-1997. Brain Inj. 2000 Apr;14(4):373-81. — View Citation

Smith EE, Jonides J, Koeppe RA. Dissociating verbal and spatial working memory using PET. Cereb Cortex. 1996 Jan-Feb;6(1):11-20. Erratum in: Cereb Cortex 1998 Dec;8(8):762. — View Citation

Stuss DT, Ely P, Hugenholtz H, Richard MT, LaRochelle S, Poirier CA, Bell I. Subtle neuropsychological deficits in patients with good recovery after closed head injury. Neurosurgery. 1985 Jul;17(1):41-7. — View Citation

Thurman DJ, Alverson C, Dunn KA, Guerrero J, Sniezek JE. Traumatic brain injury in the United States: A public health perspective. J Head Trauma Rehabil. 1999 Dec;14(6):602-15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	mPASAT		Pre-Treatment, Post-Treatment
Primary	Dispersion of fMRI signal		Pre-Treatment, Post-Treatment
Primary	Simple Vigilance Task		Pre-Treatment, Post-Treatment
Primary	Neuropsychological Battery (Digit Vigilance Task, California Verbal Learning Test, Digit Span and Continuous Performance Task)		Pre-Treatment, Post-Treatment